Mechano-sensing stem cells to study, detect and treat cancer metastases

机械传感干细胞用于研究、检测和治疗癌症转移

• 批准号: 8758634
• 负责人: Weian Zhao
• 金额: $ 231.75万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8758634
• 关键词: Adverse effects; American; Area; Blood; Cancer Patient; Cardiovascular system; Cells; Cessation of life; Choristoma; Clinical; Cloning; Collagen; Cues; Diagnosis; Diagnostic; Disease Progression; Disseminated Malignant Neoplasm; Effectiveness; Environment; Enzymes; Future; Generations; Goals; Home environment; In Situ; Life; Light; Lung; Malignant Neoplasms; Mammary Neoplasms; Measurement; Measures; Mechanics; Mesenchymal Stem Cells; Methods; Micrometastasis; Monitor; Neoplasm Metastasis; Patients; Primary Neoplasm; Property; Protein-Lysine 6-Oxidase; Reporter; Resolution; Stem cells; Symptoms; System; Technology; Testing; Therapeutic; Tissues; antitumor agent; base; chemotherapy; crosslink; high risk; imaging probe; in vivo; malignant breast neoplasm; promoter; public health relevance; response; routine practice; sensor; stem cell differentiation

DESCRIPTION (provided by applicant): Metastasis is responsible for over 90% of breast cancer deaths, however no current treatments directly target metastatic cancer. Results from decades of treatment of metastatic breast cancer patients has been bleak, with studies indicating only slight increases in survival which is often accompanied by the severe side effects of systemic chemotherapy. Recent studies have revealed that the mechanical properties of cellular microenvironments (mechano-niche), specifically stiffness, have a close relation with breast cancer metastasis. Specifically, it has been noted that the breast tumor secretes enzymes (lysyl oxidase) into the circulatory system that crosslink collagens and increase the stiffness of tissues accumulate at areas in the lung where metastases occur. Additionally, mesenchymal stem cells (MSCs) can actively and selectively home to breast cancer metastases when injected into the blood and their differentiation is tightly regulated by the stiffness of the local environment. In light of the tight correlation between tissue stiffness with breast cancer metastasis and MSC differentiation, I propose to develop a mechanoresponsive cell system (MRCS) to directly target the mechano-environmental cues of breast cancer metastases for localized and specific delivery of diagnostic reporters and anti-tumor agents. The project will involve 1) establishing the MRCS by identifying and cloning stiffness-specific promoters in MSCs. These promoters can be used to drive expression of imaging probes and therapeutics, 2) testing the ability of MRCS to detect cancer metastases and measure stiffness in metastatic niche in vivo, and 3) treating breast cancer lung metastases in vivo using MRCS through specific and local activation of therapeutics. Upon accomplishing the above goals, we will have created the first therapeutic system to directly interrogate matrix stiffness and applied it to localized delivery of agents to breast cancer metastases. This system has major clinical implications in increasing the effectiveness of therapies for the over 150,000 Americans living with metastatic breast cancer while also ameliorating the symptoms associated with systemic chemotherapy. Importantly, the proposed MRCS will serve as a platform technology for future application to therapies targeting aberrant tissue stiffness in potentially any types of cancer metastasis. Additionally, our MRCS has the potential to become a routine practice for diagnosis of micrometastases and for monitoring treatment in high-risk patient groups. Furthermore, generation of a cell-based stiffness sensor for measurement of matrix mechanical properties in situ will represent a paradigm-shifting method of dynamically interrogating the mechano-environment of primary tumors, metastases, and changes in matrix stiffness during disease progression and response to therapies at a cellular resolution in vivo.

描述（由申请人提供）：转移是导致90%以上乳腺癌死亡的原因，但是目前没有直接针对转移性癌症的治疗方法。数十年来对转移性乳腺癌患者的治疗结果令人沮丧，研究表明生存率只有轻微的增加，而这往往伴随着全身化疗的严重副作用。近年来的研究表明，细胞微环境（mechano-niche）的力学特性，特别是刚度与乳腺癌转移密切相关。具体来说，已经注意到乳腺肿瘤分泌酶（赖氨酸氧化酶）进入循环系统，交联胶原，增加组织的刚度，积聚在肺转移发生的区域。此外，骨髓间充质干细胞（MSCs）被注入血液后，可以主动和选择性地转移到乳腺癌，它们的分化受到骨髓硬度的严格调节

项目成果

Stem Cell Extracellular Vesicles: Extended Messages of Regeneration.

• DOI: 10.1146/annurev-pharmtox-061616-030146
• 发表时间: 2017-01-06
• 期刊: Annual review of pharmacology and toxicology
• 影响因子: 12.5
• 作者: Riazifar M;Pone EJ;Lötvall J;Zhao W
• 通讯作者: Zhao W

Elucidation of Exosome Migration across the Blood-Brain Barrier Model In Vitro.

• DOI: 10.1007/s12195-016-0458-3
• 发表时间: 2016-12
• 期刊: Cellular and molecular bioengineering
• 影响因子: 2.8
• 作者: Chen CC;Liu L;Ma F;Wong CW;Guo XE;Chacko JV;Farhoodi HP;Zhang SX;Zimak J;Ségaliny A;Riazifar M;Pham V;Digman MA;Pone EJ;Zhao W
• 通讯作者: Zhao W

Mesenchymal stem cells engineered to express selectin ligands and IL-10 exert enhanced therapeutic efficacy in murine experimental autoimmune encephalomyelitis.

• DOI: 10.1016/j.biomaterials.2015.11.005
• 发表时间: 2016-01
• 期刊: Biomaterials
• 影响因子: 14
• 作者: Liao W;Pham V;Liu L;Riazifar M;Pone EJ;Zhang SX;Ma F;Lu M;Walsh CM;Zhao W
• 通讯作者: Zhao W